JC virus (JCV) is a human polyoma virus for which 70% of the human population is seropositive. It is responsible for the fatal demylinating disease Progressive Multifocal Leukoencephalopathy (PML). PML occurs almost exclusively in patients with AIDS and is characterized by dementia, motor and visual deficits, coma, and finally death. This project focuses on understanding the molecular pathogenesis of PML in the setting of virus induced cytopathology in a tissue culture model. JCV contains an icosahedral capsid that consists of 72 pentamers of the major capsid protein Vp1 with a minor coat protein Vp2 or Vp3 in the center of the pentamer. It is known that Vp1 is necessary for the tropism of the virus through receptor interactions. However, little is known about the role that the minor coat proteins play in pathogenesis. In this proposal the minor coat proteins and their critical residues will be mutated and the effects of the mutations will be evaluated at distinct points in the viral life cycle. This will be done in order to test the hypothesis that the minor coat proteins are necessary for efficient viral propagation leading to cellular cytopathology and dysfunction that ultimately contributes to the pathogenesis of PML in AIDS patients.